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Biomedical subjects

B K Weir

Publications and source records attributed to B K Weir.

At least 73 records · Page 4Linked to original sources
PubMed1989

Intrathecal fibrinolytic therapy after subarachnoid hemorrhage: dosage study in a primate model and review of the literature.

Because of the naturally low fibrinolytic activity of CSF many erythrocytes entrapped in subarachnoid blood clot undergo hemolysis in situ, releasing vasogenic oxyhemoglobin (OxyHb) in high concentrations around the basal cerebral arteries. In order to promote more rapid clearance of erythrocytes from the basal subarachnoid cisterns we are currently investigating intrathecal thrombolytic therapy with human, recombinant, tissue plasminogen activator (rt-PA) in a primate model of subarachnoid hemorrhage (SAH) and cerebral vasospasm (VSP). In the present study 16 monkeys were divided into 4 groups of 4, and each group received a different dose of sustained-release gel rt-PA at the time of experimental SAH. Cerebral angiography seven days later showed that whereas no VSP occurred in the groups receiving 0.5 or 0.75 mg of rt-PA, mild to moderate VSP occurred in the groups receiving 0.125 or 0.25 mg of rt-PA. Analysis of the combined 2 smaller dosage groups revealed significant (P less than 0.05) reduction of lumen caliber in the clot-side internal carotid (C3 and C4), proximal anterior cerebral (A1) and middle cerebral (MCA) arteries. Gross subarachnoid clot remained in all of the animals in the 0.125 and 0.25 mg dose groups, in 2 of the animals in the 0.5 mg dose group, and none of the animals in the 0.75 mg dose group. It was concluded that 0.75 mg of gel rt-PA is sufficient to completely lyse a 4.25 ml SAH and prevent VSP in our primate model. The literature on fibrinolysis and erythrocyte clearance in cerebrospinal fluid (CSF) is reviewed.

Animals↗
PubMed1989

Arterial wall changes in cerebral vasospasm.

A right-sided subarachnoid hemorrhage (SAH) was created in 12 monkeys. Only the right (clot-side) cerebral arteries developed angiographic vasospasm (VSP), which was maximal 7 days after SAH. Eight animals were killed at this time and the remainder at 14 days. At the time of killing the middle cerebral arteries (MCAs) were harvested, and four normal, left (non-clot-side) MCAs were vasoconstricted in vitro with prostaglandin F2 alpha. All MCAs were studied with scanning and transmission electron microscopy. Right MCAs in maximal VSP 7 days from SAH were undistinguishable on scanning electron microscopy from normal arteries vasoconstricted in vitro: both groups demonstrated a mean 57% reduction in vessel caliber and a 5-fold increase in vessel wall thickness compared to normal, nonvasoconstricted left MCAs. On transmission electron microscopy, however, arteries in SAH-induced VSP showed degenerative changes in the tunica intima and media. These changes were still evident at 14 days, despite considerable resolution of VSP. These findings, as well as those from other pathological studies of animal and human cerebral arteries in VSP, suggest that the arterial narrowing and vessel wall thickening seen within several weeks of SAH is due primarily to medial contraction, but unlike simple vasoconstriction, is associated with degenerative ultrastructural changes in the endothelium and vascular smooth muscle cells which may denote a temporarily irreversible state.

Animals↗
PubMed1989

Time-dependent effects of extraluminally-applied oxyhemoglobin and endothelial removal on vasodilator responses in isolated, perfused canine basilar arteries.

The effects of oxyhemoglobin (oxyHb) and removal of the endothelium have been measured in isolated, perfused canine basilar arteries treated with intraluminal vasodilator drugs. In preparations with an intact endothelium, acetylcholine (ACh) produces a biphasic response, where a small vasodilation precedes a vasoconstriction. Calcium ionophore A23187 and thimerosal induce a vasodilation at low doses and a biphasic response at high doses. Sodium nitroprusside (SNP) evokes only a vasodilation. Extraluminally applied oxyHb itself produces a transient vasoconstriction and then a gradual increase in perfusion pressure. After this treatment, the vasoconstriction to ACh was enhanced as was the vasodilation to SNP. Significant attenuation of the vasodilator action of A23187 and thimerosal was also observed. Subsequent removal of endothelium produced no further change in response. This implies that the action of extraluminal oxyHb is to eliminate any endothelium-dependent responses. If cerebral vasospasm after subarachnoid hemorrhage is initiated by hemoglobin released from the clot surrounding the artery, at least one component of its action appears to involve interference with endothelial function.

Acetylcholine↗
PubMed1989

A trial of the 21-aminosteroid U74006F in a primate model of chronic cerebral vasospasm.

The efficacy of U74006F in the prophylaxis of chronic cerebral vasospasm (VSP) was evaluated in a randomized, double-blind, placebo-controlled trial. Forty cynomolgus monkeys were divided by restricted randomization into 2 treatment groups of 20. Five animals from each treatment group were randomized into subgroups 1 and 2. The animals of subgroup 1 were studied pathologically. Brain biopsies of the animals in subgroup 2 were performed and studied with high-performance liquid chromatography (HPLC). The remaining 20 animals supplemented the number studied angiographically. Significant VSP (P less than 0.05) was detected in the majority of vessels from the clot site (right) of both treatment groups. Electron microscopy results showed positive correlation with the angiographic data. When comparing the effects of U74006F to those of the placebo at day 7, there was a significant difference (P less than 0.05) in the degree of VSP in the right extradural internal carotid and right middle cerebral arteries. This resulted from a greater degree of VSP in placebo animals. Two animals developed delayed ischemic deficits, one from each group. The infarct of the U74006F animal was smaller than the infarct in the placebo animal. Although overall changes in phosphagen levels did not reach statistical significance, HPLC analysis of the cortical biopsies did show a decrease in the ATP/ADP +/- AMP ratio of 54% in placebo animals and only 7% in animals receiving U74006F. The middle cerebral arteries of 2 animals were also studied with HPLC.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Safety and efficacy of intrathecal thrombolytic therapy in a primate model of cerebral vasospasm.

To test the safety of a large intrathecal dose of human recombinant tissue plasminogen activator (rt-PA), 6 cynomolgous monkeys were given 10 mg of rt-PA (mean, 2.7 mg/kg) through an Ommaya reservoir after craniectomy and dissection of the basal cisterns. Bleeding occurred briefly at the incision in 2 animals; otherwise the clinical condition of all 6 remained normal throughout the postoperative period. Systemic fibrinolysis did not occur, and gross and microscopic examination of the brain and meninges revealed no abnormality. Next, we evaluated the efficacy of unilateral administration of rt-PA suspension (0.5 mg) plus slow-release gel rt-PA (1.25 mg) in lysing a bilateral subarachnoid clot and preventing vasospasm in a randomized, placebo-controlled trial. Sixteen monkeys were divided randomly into 2 equal groups, each of which underwent baseline cerebral angiography, followed by frontotemporal craniectomy and induction of subarachnoid hemorrhage on the left side and then on the right. Before closure on the right side either rt-PA or an equal volume of placebo was injected into the subarachnoid space. On day 7 angiography was repeated, and the animals were killed under anesthesia for necropsy. One of the animals in the placebo group developed a cerebral infarction on day 5. In the placebo group significant vasospasm occurred in all major right and left-sided anterior cerebral vessels (P less than 0.01). No vasospasm occurred in the rt-PA-treated animals. Whereas gross subarachnoid clot was found in all animals in the placebo group (mean clot weight 1.13 g), only a small fragment of clot was found in a single rt-PA-treated animal.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Pharmacological studies on relaxation of spastic primate cerebral arteries in subarachnoid hemorrhage.

Chronic cerebral vasospasm was induced in 16 monkeys by direct placement of a clot of autologous blood over the arteries of the circle of Willis on the right side. The middle cerebral arteries (MCA's) on the clot side all showed angiographic vasospasm, which was maximal 7 days after subarachnoid hemorrhage. Animals were sacrificed at this time and vascular responses to acetylcholine (ACh), histamine, and the calcium ionophore A23187 were studied in MCA rings from the clot (spastic) side and the non-clot (control) side. In control preparations with an intact endothelium, which had been precontracted by prostaglandin F2 alpha (PGF2 alpha), histamine and A23187 produced significant relaxation. The same concentrations of histamine and A23187 did not relax vascular tissues in which the endothelium had been mechanically removed. Acetylcholine did not produce a significant endothelium-dependent relaxation of primate MCA rings, but did relax rings of primate common carotid artery. Pretreatment with chlorpheniramine (an H1-receptor antagonist) prevented histamine-induced relaxation; however, cimetidine (an H2-receptor antagonist) had no inhibitory action. It thus seems that histamine mediates relaxation of intact MCA's mostly by an H1-receptor-mediated release of endothelium-derived relaxing factor (EDRF). Relaxations induced by histamine and A23187 in MCA's from the clot side were substantially reduced. Moreover, the small component of ACh-induced relaxation was also abolished. Endothelium-independent relaxation induced by glyceryl trinitrate (GTN) occurred in arteries from both the control and the clot sides. Constrictions induced by KC1 and PGF2 alpha were reduced on the clot side of the MCA's. These results suggest that subarachnoid hemorrhage influences both the generation of EDRF and the constriction of affected arteries. The small contraction which was elicited in spastic arteries was fully relaxed by GTN.

Acetylcholine↗
PubMed1988

Development of neurosurgery in Canada.

The development of neurosurgery in Canada is traced through an analysis of the contributions of key early figures in this specialty. The evolution of Canadian training standards is discussed against the background of socio-economic change in the nation at large.

Academic Medical Centers↗
PubMed1988

Intrathecal nimodipine therapy in a primate model of chronic cerebral vasospasm.

The safety, prevention, and treatment of chronic vasospasm by repeated administration of intrathecally applied nimodipine was evaluated in a primate model of chronic cerebral vasospasm. Twenty-four female cynomolgous monkeys were randomized into three groups of 8: sham, clot, and clot + intrathecal nimodipine. All animals underwent a subarachnoid hemorrhage (SAH) induction operative procedure after base line angiography. Nimodipine was administered postoperatively by subcutaneous injection of 1 ml/0.2 mg tid for 6 days through an Ommaya reservoir with the catheter placed in the subarachnoid basal cisterns. Angiography was performed on Day 7 post-SAH induction. Intrathecally applied nimodipine was not effective in the prevention of angiographic vasospasm. It also did not seem to decrease the degree of pathological change when compared to controls. One animal in the nimodipine group died 2 hours after an intrathecal injection secondary to a respiratory arrest. Transient sedation and hypoventilation were common. No adverse pathological effects were noted. Intrathecal nimodipine did not produce a significant dilation of vessels in moderate or severe spasm when assessed by angiography 2 hours after intrathecal injection. Only 1 animal in 8 showed diffuse dilation of vasospastic cerebral vessels after an intrathecal nimodipine injection. Three other animals in this group developed dilation only of the basilar artery, which was in mild spasm.

Animals↗
PubMed1988

Nimodipine treatment in poor-grade aneurysm patients. Results of a multicenter double-blind placebo-controlled trial.

A multicenter, randomized placebo-controlled double-blind trial of nimodipine in poor-grade aneurysm patients was carried out in 17 Canadian hospitals. Of 188 patients enrolled in the trial, 32 were excluded for protocol violations and two were excluded due to statistical considerations, leaving 154 patients for valid outcome analysis. Nimodipine treatment was associated with a significantly better outcome (p less than 0.001): 21 (29.2%) of 72 nimodipine-treated patients had a good outcome at 3 months after subarachnoid hemorrhage (SAH) compared to eight (9.8%) of 82 placebo-treated patients. Delayed ischemic deficits from vasospasm alone were significantly less frequent in the nimodipine group (p less than 0.05) with permanent deficits occurring in five nimodipine-treated patients (6.9%) and in 22 placebo-treated patients (26.8%). Improvement in the good outcome rate and reduction in delayed ischemic deficits from vasospasm alone occurred in both Grade 3 and 4 patients, with no difference between nimodipine- and placebo-treated patients being found in Grade 5 patients. Repeat angiography after Day 4 was carried out in 124 patients. There was no significant difference in the incidence of moderate or severe diffuse spasm, which was seen in 64.3% of nimodipine-treated patients and 66.2% of placebo-treated patients. The authors conclude that nimodipine treatment in poor-grade patients with SAH results in an increase in the number of good outcomes and a reduction in the incidence of delayed neurological deterioration due to vasospasm. This effect occurs by a mechanism other than prevention of large-vessel spasm as visualized on angiography.

Adolescent↗
PubMed1988

Effect of intrathecal thrombolytic therapy on subarachnoid clot and chronic vasospasm in a primate model of SAH.

The safety and efficacy of the thrombolytic agent tissue-type plasminogen activator (tPA) in the elimination of subarachnoid clot and prevention of chronic vasospasm were evaluated in a blind randomized placebo-controlled trial. Twenty-four monkeys were randomly assigned to one of two groups of 12. Each group underwent baseline cerebral angiography and coagulation analysis followed by right-sided craniectomy and experimental subarachnoid hemorrhage (SAH). An Ommaya reservoir was inserted with its catheter placed into the subarachnoid space. Twenty-four hours later one group (the tPA group) received 0.5 mg of tPA in 0.5 ml of buffer injected into the reservoir every 8 hours for three doses, while the second group (the placebo group) received the same volume of normal saline. On Day 7, angiography was repeated and the animals were sacrificed. One animal from the placebo group developed a delayed ischemic neurological deficit on Day 5 after SAH. Moderate to severe vasospasm (greater than 30% reduction in vessel caliber) was present on Day 7 in the internal carotid and middle cerebral arteries of the animals in the placebo group (p less than 0.01), while in the tPA group only mild narrowing of the anterior cerebral artery was seen. No significant change in coagulation status occurred in either group. All animals in the placebo group had a large amount of subarachnoid clot remaining at the time of sacrifice, but 11 of the 12 animals in the tPA group were completely free of clot. The results of electron microscopic studies of the cerebral arteries correlated with angiography, and there was no histological evidence of brain inflammation associated with the intrathecal use of tPA.

Animals↗
PubMed1987

Neuropsychological function in patients after subarachnoid hemorrhage.

Neuropsychological testing of 48 patients who had undergone operation for subarachnoid hemorrhage (SAH) due to aneurysm was performed. Before this, the patients had their level of neurological recovery classified by neurosurgeons (37 good outcome vs. 9 poor outcome). These clinical categories correlated well with the results of neuropsychological testing. The degree of psychological impairment was related to age. The mean duration between SAH and clipping of the ruptured aneurysm was 4.6 days (range, 1-16 days), and 59% had operations on or before Day 3 post-SAH. Of the 37 patients with good neurological outcome, 26 patients had good neuropsychological outcome (no more than mild deficit). Poor neuropsychological outcome was associated with age and anterior communicating artery aneurysms. The incidence of significant neuropsychological deficit was considerably less than in previous reports, and possible explanations are discussed.

Brain Damage, Chronic↗
PubMed1987

Effect of clot removal at 24 hours on chronic vasospasm after SAH in the primate model.

The efficacy of complete clot removal 24 hours after subarachnoid hemorrhage (SAH) in the prevention of chronic cerebral vasospasm was evaluated in monkeys in a blind randomized controlled trial. Twenty-four monkeys were randomized to one of three groups to undergo sham-operation (sham-operated group), clot placement only (clot group), or clot placement and removal (clot-removal group). By means of standard microsurgical techniques, the major cerebral vessels bilaterally were dissected free of arachnoid. An autologous hematoma averaging 5 gm was placed around the vessels in the subarachnoid spaces in the clot and clot-removal groups. Saline solution was instilled in the subarachnoid spaces of the sham-operated group. All animals underwent reoperation 24 hours after the first procedure. In the clot-removal group, the hematoma was evacuated. In the sham-operated and clot groups, the incision was simply closed again after 3 hours of anesthesia. Indices monitored before and 7 days after SAH induction included neurological status, angiographic cerebral vessel caliber, and arterial blood pressure. All animals were evaluated with magnetic resonance imaging (MRI); representative animals were evaluated with computerized tomography (CT) brain scans. There were no neurological deficits in either the sham-operated or the clot-removal groups. One animal in the clot group developed a progressive delayed ischemic deficit on Day 5 after SAH. A second animal in this group died suddenly on Day 4 post-SAH. An autopsy revealed a recent infarct in the territory of the superior cerebellar artery. Clinical findings correlated with MRI and CT images. Significant vasospasm (25% to 100% reduction in vessel caliber) was present on Day 7 in 100% of the clot animals (p less than 0.01). There was no significant vasospasm (p greater than 0.05) on Day 7 in either the sham-operated or the clot-removal groups. A large volume of clot placed bilaterally resulted in a 25% incidence of delayed ischemic deficit. Evacuation of subarachnoid hematoma within 24 hours of SAH prevented the development of chronic vasospasm and delayed ischemic deficit in the primate model.

Animals↗
PubMed1987

Long-term prospective study of lumbosacral discectomy.

A long-term prospective study of 100 patients undergoing lumbosacral discectomy was carried out in an attempt to delineate the natural history of these patients and to assess the relative significance of preoperative factors as determinants of long-term outcome. Neurological findings were documented preoperatively and at 1 month, 1 year, and 5 to 10 years postoperatively. A questionnaire using subjective and objective data was given to patients at 1 year and 5 to 10 years postoperatively. An 83% long-term follow-up result was obtained. At a minimum of 5 years postoperatively, 62% of patients had complete relief of back pain and 62% had complete relief of leg pain; 96% were pleased that they had submitted to surgery and 93% were able to return to work. Nine percent reported that their back pain at 5 to 10 years was as severe as or worse than preoperatively and 11% reported that their leg pain was as severe as or worse than preoperatively. The reoperation rate was 18%. Preoperative factors found to be significantly associated with outcome at 1 year postoperatively were not significantly associated with outcome at 5 to 10 years postoperatively. The results of lumbosacral discectomy appear favorable as evaluated in this study. Preoperative factors useful as predictors of short-term outcome are much less reliable when considering the long-term results.

Adult↗
PubMed1987

The effect of timing of clot removal on chronic vasospasm in a primate model.

The effect of complete clot removal at times from 48 to 96 hours after subarachnoid hemorrhage (SAH) on the development of chronic cerebral vasospasm was evaluated to determine whether there is a critical point after which clot removal is ineffective in preventing vasospasm. Thirty cynomolgus monkeys were randomized to one of five groups: sham-operated group, clot removal at 48 hours after SAH (48-hour group), clot removal at 72 hours after SAH (72-hour group), clot removal at 96 hours after SAH (96-hour group), and clot placement only (clot group). Standard microsurgical techniques were used to dissect bilaterally the major cerebral arteries free of arachnoid. An autologous blood clot averaging 4.2 gm was placed around the vessels in the subarachnoid space of the monkeys in the 48-hour, 72-hour, 96-hour, and clot groups. Physiological saline was instilled into the subarachnoid space of the sham-operated animals. Animals in the clot-removal groups underwent surgical clot removal at the determined times for each group. Two animals in each of the sham-operated and clot groups were subjected to reoperation at each of 48, 72, and 96 hours after SAH. The incisions were reopened and then simply reclosed. Neurological status, angiographic cerebral vessel caliber, and physiological status were evaluated before and 7 days after SAH induction. There were no significant neurological deficits in the sham-operated, 48-hour, or 72-hour groups. Two animals in each of the 96-hour and clot groups showed deterioration in level of consciousness developing on Day 4 or 5 after SAH induction. All the major cerebral arteries of the animals in the clot and 96-hour groups showed significant vasospasm (p less than 0.01) on Day 7. Animals in the 72-hour group had significant vasospasm (p less than 0.05) of the internal carotid and middle cerebral arteries but not the anterior cerebral arteries. There was no significant vasospasm (p greater than 0.05) in any of the cerebral arteries in the 48-hour group. Severity of vasospasm paralleled the duration of contact between the blood clot and the cerebral vessels. Evacuation of the subarachnoid hematoma later than 48 hours after SAH resulted in no significant reduction in the degree of chronic cerebral vasospasm. It is suggested that clot removal at early operation is likely to be useful only if it is performed within 48 hours of SAH.

Animals↗
PubMed1986

Effects of nimodipine on in vitro contractility of cerebral arteries of dog, monkey, and man.

Cerebrovascular spasm in the cynomolgus monkey does not appear to be modified by nimodipine. It is possible that cerebral arteries from this species are unusually resistant to the action of calcium antagonists. To test this hypothesis, parallel studies on the in vitro response of cerebral arteries from monkey, dog, and man have been carried out. Rings of basilar or middle cerebral artery were tested with potassium chloride, noradrenaline, 5-hydroxytryptamine, prostaglandin F2 alpha, and hemoglobin. The responses were then reexamined in the presence of various concentrations of nimodipine. There is a significant variation among species in sensitivity to nimodipine, the vessels from the monkey being more resistant to nimodipine than those from other species. There is, as expected, a considerable difference in the ability of nimodipine to block the different agonists. Responses to potassium chloride are blocked by low concentrations of nimodipine in all species, whereas noradrenaline and 5-hydroxytryptamine are more resistant. It is noteworthy that, in all species tested, hemoglobin and prostaglandin F2 alpha were antagonized poorly even by higher concentrations of nimodipine. If these agonists play a major role in the development of vasospasm and subsequent delayed ischemia, it may be that the calcium antagonists exert a beneficial effect by some mechanism other than dilation of spastic arteries.

Animals↗
PubMed1983

Cerebral arterial spasm--a controlled trial of nimodipine in patients with subarachnoid hemorrhage.

We enrolled 125 neurologically normal patients with intracranial aneurysms in a multi-institution, prospective, double-blind, randomized, placebo-controlled trial within 96 hours of their subarachnoid hemorrhage, to determine whether treatment with the calcium blocker nimodipine would prevent or reduce the severity of ischemic neurologic deficits from arterial spasm. A deficit from cerebral arterial spasm that persisted and was severe or caused death by the end of the 21-day treatment period occurred in 8 of 60 patients given placebo and in 1 of 56 given nimodipine (P = 0.03, Fisher's exact test). Analysis of the amount of basal subarachnoid blood on pre-entry CAT scans in patients with deficits from spasm showed that an increase in subarachnoid blood was not associated with a worse neurologic outcome among patients who received nimodipine, unlike the situation in patients given a placebo. There were no side effects from nimodipine. We conclude that nimodipine should be given to patients who are neurologically normal after subarachnoid hemorrhage in order to reduce the occurrence of severe neurologic deficits due to cerebral arterial spasm.

Adolescent↗
PubMed1983

Results of burr hole and open or closed suction drainage for chronic subdural hematomas in adults.

Chronic subdural hematomas in adults are not technically difficult to treat. They probably constitute one of the most common potentially curable lesions with which the average neurosurgeon deals. Despite this (or perhaps because of it) numerous treatments, radically differing from one another, have been advocated. Fine judgment is called for in deciding whether or not to operate in the first instance, make a flap or one or more burr or twist drill holes, use a drain, employ suction, inflate the brain, leave the bone flap out. In a personal series of 71 chronic subdural hematomas, 46 were treated with a red rubber catheter drain through a burr hole and 23 with a closed system suction drain. The results of this series suggest that closed system suction drainage through a single burr hole is the better of the two techniques. It has important theoretical advantages and the procedure is simple and fast. The complication rate is low and patients have a shortened postoperative hospital stay.

Chronic Disease↗